The compound N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(1-methyl-1-{[(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl]amino}ethyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (hereinafter referred to as “raltegravir”) is a potent HIV integrase inhibitor. The structure of raltegravir is as follows:
Raltegravir, disclosed in U.S. Pat. No. 7,169,780, is the active pharmaceutical ingredient (API) in Isentress® tablets. The tablets contain 400 mg of raltegravir in the form of a potassium salt and are approved by the FDA in combination with other anti-retroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection in adult patients. Isentress® is a first-in-class drug product and an important weapon in the arsenal of drugs available for treating HIV infection. A useful complement to Isentress® would be a raltegravir-containing tablet that is smaller in weight and volume and characterized by providing an improved pharmacokinetic profile.
The following references are of interest as background:
US 2006/0122205 A1 discloses crystalline potassium salts of raltegravir.
US 2007/0292504 A1 discloses pharmaceutical formulations for oral administration in solid dosage forms that contain a base salt of raltegravir and a release rate controlling composition. Example 3 describes the preparation via a dry granulation process of compressed tablets containing raltegravir potassium salt (400 mg free phenol), microcrystalline cellulose, lactose hydrous spray dried, anhydrous dibasic calcium phosphate, HPMC K4M, poloxamer 407, sodium stearyl fumarate, and magnesium stearate.
US 2008/0118559 A1 discloses pharmaceutical formulations for oral administration in solid dosage forms that contain an alkali metal salt of raltegravir and an anti-nucleating agent. Example 3 describes the preparation via a dry granulation process of compressed tablets containing raltegravir potassium salt (100 mg and 25 wt. % on a free phenol basis), microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, HPMC 2910 (6 cp), and magnesium stearate. Example 6 describes the preparation via dry granulation of compressed tablets film-coated with Opadry White and containing raltegravir potassium salt (400 mg and 50 wt. % on a free phenol basis), microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, HPMC 2910 (6 cp), and magnesium stearate.
WO 2009/002823 A2 discloses compressed tablets comprising raltegravir and granules containing atazanavir sulfate and an intragranular lubricant, wherein the granules have an interior section and an exterior surface and at least a portion of the intragranular lubricant is present in the interior section of the granules. The compressed tablets are useful for treating HIV infection.